Heroin dependence has reemerged as a significant public health problem in the 1990's. Detoxification is and will continue to be a common first step in the treatment of individuals with heroin dependence, but the two detoxification approaches in widespread use today, the methadone taper and clonidine-assisted detoxification, are flawed. There is a need for new pharmacological approaches to heroin detoxification. The research proposed here aims to develop and implement a model screening procedure to evaluate potentially promising new medications for use in heroin detoxification. Our approach is to carry out a series of three 7-day, three- arm randomized, double-blind clinical trials, each one comparing two matched promising medications for opioid detoxification with a clonidine- assisted detoxification. We incorporate a comprehensive assessment of withdrawal Severity, cognitive and motor performance, and follow-up data four weeks following entry into the study. Our first study compares two medications, a potentially less hypotensive alpha-2 agonist, lofexidine, and a calcium channel antagonist, isradipine, directly with clonidine-assisted detoxification. Our second trial examines the potential utility of NMDA antagonists by comparing two noncompetitive NMDA antagonists, memantine and dextromethorphan, with clonidine. The third trial investigates the role of partial mu opioid agonists with differential kappa activities by comparing buprenorphine and butorphanol with clonidine. The strength of our approach lies in the controlled evaluation of potentially promising detoxification medications under consistent conditions. We expect to provide information about new mechanisms for medications development for opioid detoxification. We focus on the role heroin detoxification procedures may have in maximizing the likelihood of opioid abstinence and treatment retention following detoxification. While we recognize that detoxification is only the first step in treatment, we also believe that improving this procedure could increase the number of heroin- dependent individuals entering it, completing it, and continuing after it with more definitive treatment.